This invention relates to diagnosis of Alzheimer's disease.
Alzheimer's disease (AD) is a devastating impairment of cognitive function prevalent in individuals generally forty-five or older. The cause of AD is not known, nor is there a treatment for AD. However, AD is the first common disease for which allelic variation or mutations at multiple genetic loci are linked to the development of disease in affected families (Roses, Annu. Rev. Med. 47: 387, 1996; Schellenberg, Proc. Natl. Acad. Sci. USA, 92: 8552, 1995). The majority (70-80%) of heritable, early-onset AD maps to chromosome 14 and appears to result from one of more than 20 different amino-acid substitutions within presenilin-1 (PS1) (Schellenberg et al., Science, 258: 668, 1992; Alzheimer's Disease Collaborative Group, Nature Genet, 11: 219, 1995; Sobi et al., Lancet., 346: 439, 1995; Van Broeckhoven, Nature Genet., 11: 230, 1995; Wasco et al., Nature Med., 1: 848, 1995; Sherrington et al., Nature, 375: 754, 1995), the product of the recently identified S182 gene (Sherrington et al., 1995). A similar, although less common, AD-risk locus on chromosome 1 encodes the highly homologous presenilin-2 (Levy-Lahad et al., Science, 269: 970, 1995; Levy-Lahad et al., Science, 269: 973, 1995; Li et al., Proc. Natl. Acad. Sci. USA, 92: 12180, 1995; Rogaev et al., Nature, 376: 775, 1995). Several amino-acid substitutions have been identified within PS2 that appear to be causative for early-onset AD (Levy-Lahad et al., Science, 269: 973, 1995; Li et al., Proc. Natl. Acad. Sci. USA, 92: 12180, 1995; Rogaev et al., Nature, 376: 775, 1995). Based upon mRNA detection, the presenilins appear to be ubiquitously expressed, suggesting that they are housekeeping proteins required by many cell types.
The two mammalian presenilins share 67% amino-acid identity and apparently belong to a larger gene-family of multimembrane spanning proteins that includes the C. elegans spe-4 and sel-12 genes. Mutations in the spe-4 gene disrupt the formation of a Golgi-derived storage and delivery organelle required for spermatogenesis in the nematode (L'Hernault et al., J. Cell Bio., 119: 55, 1992). SEL-12 has been shown to facilitate signaling by lin-12, a member of the Notch family of transmembrane receptors critical for cell surface to nucleus signaling during development (Levitan et al., Nature, 377: 351, 1995). A possible ER and/or Golgi localization of epitope-tagged constructs overexpressed in cultured cells and a similar immunolabeling pattern reported in mouse pyramidal neurons are consistent with the presenilins being integral membrane proteins found within compartments of the secretory pathway (Kovacs et al., Nature Med., 224: 224, 1996; Moussaoui et al., FEBS Letters, 383: 219, 1996). This, in conjunction with the spe-4 phenotype and the known importance of membrane proteins and their compartmentalization in AD, has led to the conjecture that the presenilins play a role in membrane protein trafficking and/or processing along the secretory pathway (Kovacs et al., Nature Med., 224: 224, 1996; Pellegrew et al., in Alzheimer disease, eds. R. D. Terry, R. Katzman, and K. L. Bick, Raven Press, New York, 1994; Harrison, Lancet, 346: 388, 1995). However, no direct evidence currently exists ascribing such a function to the presenilins, nor is there evidence suggesting any specialized role for presenilins in the brain. Finally, the broad distribution of the identified AD-causing mutations throughout PS1 and PS2 has yet to suggest any clear mechanistic link between these mutations and the disease process (Van Broeckhoven, Nature Genet., 11: 230, 1995).